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The role of BRAF V600 mutation in melanoma

Paolo A Ascierto18*, John M Kirkwood2, Jean-Jacques Grob3, Ester Simeone1, Antonio M Grimaldi1, Michele Maio4, Giuseppe Palmieri5, Alessandro Testori6, Francesco M Marincola7 and Nicola Mozzillo1

Author Affiliations

1 Department of Melanoma, Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy

2 Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

3 Hopital de la Timone, and Aix-Marseille Univ, 264 Rue St Pierre, 13885, Marseille CEDEX 05, Marseille, France

4 Medical Oncology and Immunotherapy, Department. of Oncology, University Hospital of of Siena, Istituto Toscano Tumori, Siena, Italy

5 Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council (CNR), Sassari, Italy

6 Melanoma and muscle-cutaneous sarcomas Division, Istituto Europeo di Oncologia, Milan, Italy

7 Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Center for Human Immunology (CHI), NIH, Bethesda, MD, USA

8 Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, Via Mariano Semmola, 80131, Naples, Italy

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Journal of Translational Medicine 2012, 10:85  doi:10.1186/1479-5876-10-85

Published: 3 May 2012


BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

BRAF; Vemurafenib; Melanoma